Certain environmental toxins, chemicals of agricultural importance, as well as, drugs and industrial chemicals are capable of inducing dose dependent renal necrosis that is primarily confined to the proximal of the nephron. Our objectives are twofold: First we plan to delineate, quantitatively and simultaneously, the acute chemically induced changes in renal function and renal morphology with the goal of determining what parameters are the most sensitive indicators of early chemically induced proximal tubular necrosis. The various chemicals cited herein will be administered to either rabbits or dogs, and the renal function will be monitored on a continuous basis for periods of 2, 4, 6, 12, and 24 hours. During this period we will determine the chemical-induced changes in the GFR, urine flow rate, urine osmolality and the renal excretion rate of Na ion, K ion, H ion, Cl ion urate, glucose and protein. At the end of the 2, 4, 6, 12, and 24 hour studies the kidneys will be fixed by the intravascular perfusion technique and the kidney tissue will be examined by light and electron microscopic techniques. Second, we plan to delineate the mechanism by which certain environmental toxins, drugs, and other cited chemicals induce specific proximal tubular necrosis. We hypothesize that many chemicals induce specific damage to only proximal tubular cells because they possess two common features: 1) an anionic or cationic group that allows for their transport into proximal tubular cells by transport systems that are confined only to the proximal tubular cells, and 2) alkylating properties (or are converted to substances with alkylating properties within proximal tubular cells). We plan to test this hypothesis using three approaches. a) We have designed, and plan to synthesize, closely related non-alkylating derivatives of various proximal tubular toxins for the purpose of evaluating their nephrotoxicity. b) We plan to determine if the intrarenal distribution of certain radiolabelled proximal tubular toxins is confined only to proximal tubular cells, and if they are bound to renal tissue in a irreversible fashion. c) Attempts will be made to modify or obliterate the necrosis induced by certain proximal tubular toxins by pretreatment with compounds that alter the proximal tubular transport of anions or cations (i.e. probenecid) or act as scavengers of alkylating agents (i.e., thiols).